The debrisoquine/sparteine genetic polymorphism is due to a number of mutant alleles of the CYP2D6 gene. This polymorphism, which affects about 7.5% of Caucasians, results in the inability to metabolize a large number of drugs. Of most serious clinical importance are the antiarrythmic drugs. A variant allele designated CYP2D6(C) was identified by analysis of a human liver characterized as being deficient in bufuralol metabolism. This liver was used to clone CYP2D6(C) cDNA. The variant cDNA encoded a protein that lacked an amino acid but otherwise was catalytically active. This protein had a different relative molecular weight on SDS- polyacrylamide gels and may be unstable in the cell. Analysis of leukocyte DNAs using a specific PCR test revealed that the CYP2D6(C) was a rare allele representing less than 1.5% of all mutant alleles. In Asian subjects, the debrisoquine/sparteine polymorphism is very rare, afflicting less than 0.5% of the population. The few poor metabolizers found in a Japanese population possess a unique allele that is in linkage disequilibrium with a Bam H1 restriction fragment length polymorphism not found in Caucasians. This allele is presumably defective. To determine the nature of this defective allele, the CYP2D6 gene was cloned from the leukocyte DNA of Japanese having low sparteine metabolism and its exons were sequenced. A G to A mutation was identified at the junction of intron 4 and exon 5, resulting in a defective 3' splice recognition site. This mutation is identical to the major CYP2C6(B) allele mutation in Caucasians. However, another base change was found in the mutant Japanese allele that was not seen in CYP2C6(B).